Mammalian animals need to take in external sources of nutrition and many transport proteins are known to exist in their cells. Many peptide transporters (peptide transport proteins; PepTs) that carry out peptide transport have been found to date (for example, J. Biol. Chem., 270(12):6456-6463, (1995); Biochim. Biophys. Acta., 1235:461-466, (1995); Mol. Microbiol., Vol. 16, p 825, (1995); Unexamined Published Japanese Patent Application No. (JP-A) Hei 6-261761; JP-A Hei 11-172; and U.S. Pat. No. 5,849,525). PepT can be classified into proteins that import peptides into cells and proteins that export peptides from cells. They can also be classified according to the different energy sources used during transport. Proton-driven PepTs, which carry out transport by utilizing protein gradient, belong to the PTR family (Mol. Microbiol., Vol. 16, p 825, (1995)). PepTs that carry out transport using ATP in the body belong to the ABC family (Annu. Rev. Cell. Biol., Vol. 8, p 67, (1992)).
There are reports that PepTs are involved in the transport of not only small-molecule peptides such as dipeptides and tripeptides, but also of pharmaceutical agents such as β-lactam antibiotics and ACE inhibitors (Ganapathy, Leibach., Curr. Biol. 3, 695-701, (1991); Nakashima et al., Biochem. Pharm. 33, 3345-3352, (1984); Friedman, Amidon., Pharm. Res., 6, 1043-1047, (1989); Okano et al., J. Biol. Chem., 261, 14130-14134, (1986); Muranushi et al., Pharm. Res., 6, 308-312, (1989); Friedman, Amidon., J. Control. Rel., 13, 141-146, (1990)).
PepT1 and PepT2 are proton-driven PepTs that contribute to the absorption of proteins and the maintenance of peptidic nitrogen sources by uptaking small-molecule peptides into cells. PepT1 and PepT2 are 12-transmembrane proteins, comprising 708 and 729 amino acids, respectively (J. Biol. Chem., 270(12):6456-6463, (1995); Biochim. Biophys. Acta., 1235:461-466, (1995); and Terada and Inui, Tanpakusitsu Kakusan Kouso., Vol. 46, No. 5, (2001)).
There are reports that PepT1 and PepT2 also transport pharmaceuticals such as β-lactam antibiotics and bestatin (Saito, H. et al., J. Pharmacol. Exp. Ther., 275, 1631-1637, (1995); Saito, H. et al., Biochim. Biophys. Acta., 1280, 173-177, (1996); and Terada, T. et al., J. Pharmacol. Exp. Ther., 281, 1415-1421 (1997)).
PepT1 is mainly expressed in the small intestine and its expression has been confirmed in the kidney and pancreas. Expression of PepT2 has been confirmed in the kidney, brain, lung, and spleen. PepT1 and PepT2 have been reported to be localized in the brush border membrane of intestinal and renal epithelial cells (Ogihara, H. et al., Biochem. Biophys. Res. Commun. 220, 848-852, (1996); Takahashi, K. et al., J. Pharmacol. Exp. Ther., 286, 1037-1042 (1998); Hong, S. et al., Am. J. Physiol. Renal. Physiol., 276, F658-F665 (1999); and Terada and Inui, Tanpakusitsu Kakusan Kouso., Vol. 46, No. 5, (2001)).
Furthermore, overexpression of PepT1 in the cell membrane of human pancreatic duct carcinoma cell lines (Cancer Res., 58, 519-525, (1998)) and the expression of PepT2 mRNA in human pancreatic duct carcinoma cell lines (Millennium World Congress of Pharmaceutical Sciences, (2000)) have been reported. However, the involvement of PepT1 and PepT2 in cancer cell growth was unclear and no discussion had been made as to whether PepT1 and PepT2 when used as target antigens against antibodies will affect cancer cell proliferation.